REPLY:

We thank Drs. Siegel, Stabin, and Sparks for their thoughtful and detailed comments on whole-body and red marrow dosimetry methods. If dosimetry is to be used as a prognostic tool, it is correct to assert that reasonable attempts should be made, when possible, both to refine the dosimetric models and to acquire accurate patient-specific data.

Our recent publication (1) was based on results dating back 15 years. We nonetheless considered the data of interest and published the results from the dosimetry methods in existence at the time. Current protocols for ¹³¹I-metaiodobenzylguanidine (MIBG) therapy at the University of California, San Francisco (UCSF), have improved the accuracy of whole-body measurements in several ways. First, we have mounted a 5-atm digital ion chamber (model 451P;Inovision, Cleveland, OH) over the patient’s bed. This device, along with an Excel (Microsoft, Redmond, WA) add-in program, permits whole-body data acquisition at frequent desired intervals. We are now able to analyze the wash-in and washout curves using hundreds of data points. Second, a power function is used to interpolate S values for total body to red marrow on the basis of patient weight. The power function, mGy/GBq-s = 0.03296 × kg^(−0.8917), where r = 0.99983, was derived by fitting the MIRD S values for total body to red marrow versus the nominal whole-body mass of the 6 MIRD phantoms. Third, the 10%–25% of the administered activity excreted in the urine during the 2-h infusion is now measured in each patient. Subtracting this activity from the infused activity more accurately defines the y-intercept of the washout curve.

Regarding the comments on total-body dose, the above refinements will optimistically decrease both variability for patients who receive multiple ¹³¹I-MIBG therapies and variability within a population of patients. Unfortunately, other factors are involved in the correlation between red marrow dose, hematologic toxicity, and administered activity. In addition, approximately 65% of ¹³¹I-MIBG is associated with the remainder, and the contribution from the remainder to the red marrow based on the MIRDOSE3 and International Commission on Radiological Protection-53 biokinetic is 90.5% for a 5-y-old child. Also, the association between glomerular filtration rate, creatinine clearance, and whole-body ¹³¹I-MIBG kinetics is well documented (2). Patients who have compromised renal function were not eligible for this study.

Identifying and understanding the numerous elements required to determine the red marrow dose that has a predictive value is beyond the scope of our clinical studies. However, we would like to respond to the comments on red marrow dose.

First, the correction factor of 0.2–0.4 that Drs. Siegel, Stabin, and Sparks cite is for 150-kDa antibodies (3), not 324-molecular-weight cations with a pKa of approximately 12. The equilibrium of ¹³¹I-MIBG from the plasma space into the hematopoietic parenchyma and supporting stroma is unknown. In fact, quoting Siegel, “Pharmacokinetic principles indicate that traffic of molecules through the fenestrations of the endothelial layer depends at least on differences in electric charge between the endothelial layer and the molecule, molecular size… ” (3). Furthermore, it is common knowledge that highly charged and polar molecules do not readily cross cell membranes.

Second, although we have never sampled red marrow from our pediatric patients to evaluate active uptake, we do know from viewing the marrow space in more than 3,000 diagnostic ¹²³I-MIBG scans since 1985 that, in the absence of disease, ¹²³I-MIBG does not concentrate in the red marrow. Our laboratory is anxiously awaiting the availability of ¹²⁴I-MIBG that will permit us to quantitatively address this issue using PET.

Third, our lack of a blood component was not an oversight. Blood samples taken 30 min after a bolus injection of ¹³¹I-MIBG containing <0.1% free iodide, from patients with normal organ function, demonstrate a very small fraction of a percentage of the administered activity. Also, dynamic scintigraphic studies dramatically demonstrate clear images of normal organs and extensive kidney and bladder activity within minutes after a bolus injection of ¹²³I-MIBG. The above blood and scintigraphic data indicate an apparent first-pass plasma clearance of MIBG. This phenomenon has been previously reported (4).

As stated in our article (1), therapeutic amounts of ¹³¹I-MIBG are infused over a 2-h period at a constant rate. Blood samples taken at 15-min intervals during the 2-h infusion and immediately afterward likewise demonstrated an extremely rapid blood clearance. For instance, the activity per gram of blood at 15, 30, 45, 60, 75, 90, 105, and 120 min during a constant rate infusion of 10.10 GBq was 46.99, 84.73, 88.80, 98.05, 120.62, 135.05, 136.90, and 144.67 kBq, respectively. At 1 and 2 h after the infusion, the activity was 49.58 and 18.50 kBq. The area under the curve of the 2-h infusion in this example was 196.10 kBq-h with a beta dose per gram of blood of approximately 2.0 cGy.

A plausible explanation for the rapid plasma clearance of ¹³¹I-MIBG is as follows:First, ¹³¹I-MIBG is a metabolically stable analog of norepinephrine; second, the concentration of catecholamines in both extracellular fluid and plasma is critical to body function; third, catecholamines are known to be highly polar chemicals that do not readily cross cell membranes; and fourth, there is a class of nonneuronal transporters that enable the body to rapidly clear and regulate catecholamine concentration in the blood (5). In humans, the organic cation transporters (OCT-1) are expressed primarily in the liver. The strategic localization of OCT-1 in an excretory organ is to eliminate specific substrates, of which ¹³¹I-MIBG is one, into the bile. However, ¹³¹I-MIBG is one of several substrates that the liver seems to lack the mechanisms to extract into the bile. A knockout mouse line that lacks functional OCT-1 demonstrated an approximately 4-fold reduction of ¹³¹I-MIBG in the liver over functional controls (5).

Dynamic scintigraphic studies demonstrate clear images of normal organs, that is, extensive liver uptake within minutes after a bolus injection of ¹²³I-MIBG. They do not, with the exception of a momentary blush, demonstrate tumor. Blake et al. state that “Following the initial rapid clearance a quasistatic equilibrium is maintained between continuing rapid plasma clearance and ¹²³I-MIBG re-entering the circulation” (2). It is our conjecture that the liver functions as a margination pool for tumor ¹²³I-MIBG uptake.

The goal of our ¹³¹I-MIBG treatment program has been to try to cure a highly malignant childhood cancer by giving the maximally effective doses. Ideally, pretherapy dosimetry should be used to predict both bone marrow toxicity and expected tumor absorbed doses for all radiotargeted isotope therapy. In fact, pretherapy dosimetry would also be ideal with all medical therapies to adjust them to individual pharmacokinetics and tolerance in each patient, but practicality and the goal of cure often dictate the use of the maximum tolerated dose determined in a phase I study, the approach that we took with ¹³¹I-MIBG. Unfortunately, the many parameters inherent in tumor dosimetry and the as yet nonmeasurable biologic factors that may contribute to tumor response and to marrow toxicity make dosimetry a less than accurate exercise. We are well aware of these biologic variations in patient bone marrow reserve, ¹³¹I-MIBG distribution and excretion, and tumor heterogeneity, after performing 139 high-dose ¹³¹I-MIBG therapies here at UCSF. Nonetheless, we have initiated a new pretherapy dosimetry protocol for ¹³¹I-MIBG to study early time-points and thus see if it is possible to improve the accuracy of predicting tumor and liver dose in each patient. As the imaging technology continues to improve, it is likely that dosimetric measurements may become more predictive of tumor response. However, the difficulty in estimating the impact on bone marrow stroma of prior therapy and infiltrating tumor will continue to confound toxicity predictions and make even the most accurate prediction of red marrow dose only an approximation for selecting a “safe” level of activity.